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Evaluation of the cyclic combination chemotherapy protocol including doxorubicin effects on cardiac parameters

Guy Tater

Doxorubicin is a commonly used chemotherapy agent for the treatment of canine malignant lymphoma. It is reported to induce cardiotoxic effects when administered in high doses. The aim of this work was to examine whether any cardiac effects can be documented following doxorubicin administration as part of a cyclic

chemotherapy protocol. Dogs were recruited for this work after being diagnosed with canine malignant lymphoma and undergoing a cyclic combination chemotherapy protocol including L-asparaginase, vincristine, cyclophosphamide, prednisolone and doxorubicin.

The first part of this work retrospectively analysed the echocardiographic records of 108 patients. LVFS as the most commonly reported and used method to detect doxorubicin cardiotoxicity, was examined.

Records of dogs presented between the years 2001 to 2010 were reviewed and 446 LVFS measurements from 108 dogs were included. No significant change of the LVFS was documented along the different stages of the chemotherapy protocol. The lower reference value used for LVFS of 25% was not exceeded.

The second part of this work included a prospective study. The aim of this study was to use more advanced and sensitive methods to detect possible cardiac changes and/or damage during the cyclic combination protocol. Fourteen dogs were included.

Blood work was performed prior to inclusion to exclude kidney damage. All dogs underwent an echocardiography examination and ultrasensitive Troponin I sampling prior and post doxorubicin administrations. The echocardiographic examination included standard as well as tissue velocity imaging measurements.

Systolic and diastolic velocity images were examined on interventricular septum and free wall. A total of 182 TVI and 1017 ultrasensitive Tropinin I measurements were performed and evaluated. During the twelve week cyclic combination protocol, Tissue Doppler indices and ultrasensitive Troponin I measurements did not change

significantly.

These findings conclude that the cyclic combination protocol seems to be safe, and no evidence of myocardial damage was detectable using echocardiographic or ultrasensitive Troponin I measurements. Further larger prospective studies should evaluate suspected doxorubicin induced myocardial damage, using sensitive new methods such as strain, strain rate and speckle tracking. Myocardial damage at the cellular level could not be excluded but if present it did not appear to have a clinical impact on the population of dogs included in this work.

V. Zusammenfassung

Evaluierung des Effekts eines Doxorubicin-beinhaltendes Zyklischen Kombinationschemotherapie-Protokolls auf kardiale Parameter.

Guy Tater

Doxorubicin ist zur Behandlung des malignen Lymphoms des Hundes ein häufig angewendetes Chemotherapeutikum. In hohen Dosen verabreicht kann eine kardiotoxische Wirkung beobachtet werden. Ziel dieser Arbeit war es zu

untersuchen ob, bei Anwendung eines zyklischen Chemotherapie-Protokolls zur Behandlung des canines Lymphoms ein Effekt auf das Herz nach Anwendung dieses Medikaments festgestellt werden kann. Hunde, bei denen die Diagnose canines malignes Lymphom gestellt wurde und die mit einem zyklischen

Chemotherapie-Protokoll mit L-Asparaginase, Vincristin, Cyclophosphamid, Prednisolon und Doxorubicin behandelt wurden, wurden in die Studie eingeschlossen.

Im ersten Teil dieser Arbeit erfolgte die retrospektive Auswertung und Analyse von echokardiographischen Aufnahmen, wobei eine mögliche doxorubicin-induzierte Kardiotoxizität anhand der LVFS untersucht wurde.

Die Aufnahmen von zwischen 2001 und 2010 vorstellig gewordenen Hunden wurden untersucht und insgesamt 446 LVFS Messungen von 108 Hunden in die Studie eingeschlossen. Es konnte kein signifikanter Unterschied der LVFS in den verschiedenen Stadien des chemotherapeutischen Protokolls festgestellt werden.

Der gebräuchliche Referenzwert der LVFS von mindestens 25 % wurde nicht unterschritten.

Der zweite Teil dieser Arbeit umfasste eine prospektive Studie. Ziel dieser Studie war es, sensitivere und ausgereiftere Methoden, die mögliche Veränderungen bzw.

Schäden am Herzen durch das zyklische Kombinationsprotokoll feststellen sollten, zu evaluieren. Vierzehn Hunde wurden eingeschlossen, bei denen zuvor erhöhte Nierenwerte anhand eines Blutbildes ausgeschlossen worden waren. Des Weiteren wurde von allen Studienteilnehmern ein Herzultraschall angefertigt und

ultrasensitives Troponin I vor und nach Doxorubicin-Gabe gemessen.

Die Ultraschalluntersuchung beinhaltete Standard- und Gewebedoppler-Messungen.

Systolische und diastolische Gewebegeschwindigkeiten des interventrikulären Septums und der freien Wand wurden untersucht. Insgesamt wurden 182 Gewebegeschwindigkeits- und 1017 ultrasensitive Troponin I Messungen durchgeführt und bewertet.

Während des zwölfwöchigen zyklischen Kombinationsprotokolls wiesen weder die Gewebedoppler-Messungen noch die Messungen des ultrasensitiven Troponin I signifikante Unterschiede auf.

Ob Doxorubicin einen myokardialen Schaden verursacht sollte anhand

weiterführender prospektiver Studien beurteilt werden, in denen andere sensitive Messmethoden wie die Strain, Strain Rate und das Speckle Tracking zum Einsatz kommen. Auch wenn es innerhalb der Studienpopulation keinen Hinweis gab, lässt sich ein Schaden des Myokards auf zellulärer Ebene durch die eigene Studie nicht mit Sicherheit ausschließen.

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WESS, G., J. SIMAK, M. MAHLING and K. HARTMANN (2010c):

Cardiac troponin I in Doberman Pinschers with cardiomyopathy.

Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 24, 843-849

VII. Tables and figures for Chapter II.1

Abb. 1 Right parasternal long axis view depicting an M-Mode. The cursor is placed along the long and short axis view at end diastole and end systole. IVSd = intraventricular septum diameter in diastole, IVSs = intraventricular septum diameter in systole, LVIDd = left ventricular inner diameter in the diastole, LVIDs = left ventricular inner diameter in the systole, LVPWd = left ventricular posterior wall diameter in diastole, LVPWs = left ventricular posterior wall diameter in systole, FS = left ventricular fractional shortening.

Tab. 1 12-week chemotherapy protocol used for the treatment of canine lymphoma as described by Simon et al.

Week

Drug Dose 1 2 3 4 5 6 7 8 9 10 11 12 13

L-asparaginasea 400 IU/kg SC

Vincristine 0.7 mg/m2 IV

Cyclophosphamide 200 mg/m2 IV

Doxorubicinb 30 mg/m2 IV*

Prednisolone

50 mg/m2 PO q24h for 3

days ● ● ● ● ● ● ● ● ●

Echocardiography

IV, intravenous administration; IV*, intravenous infusion over 30 min; PO, oral administration

aPretreatment with prednisolon

bAdministration of prednisolone on days 1-3

Tab. 2 Table showing left ventricular fractional shortening (LVFS) changes of the four groups during the cyclic combination chemotherapy protocol including doxorubicin.

Groups Measurement LVFS (min-max)

Group 1 (one DT) (n = 7) median baseline LVFS (%) 33 (26-40) median LVFS post 1 DT (%) 30 (27-37) Group 2 (two DT) (n = 17) median baseline LVFS (%) 33 (20-49) median LVFS post 1 DT (%) 34 (25-43) median LVFS post 2 DT (%) 31 (25-43) Group 3 (three DT) (n = 39) median baseline LVFS (%) 35 (24-50) median LVFS post 1 DT (%) 34 (25-50) median LVFS post 2 DT (%) 34 (25-50) median LVFS post 3 DT (%) 32 (22-43) Group 4 (four DT) (n = 45) median baseline LVFS (%) 32 (22-49) median LVFS post 1 DT (%) 32 (24-54)

Group 1 (one DT) (n = 7) median baseline LVFS (%) 33 (26-40) median LVFS post 1 DT (%) 30 (27-37) Group 2 (two DT) (n = 17) median baseline LVFS (%) 33 (20-49) median LVFS post 1 DT (%) 34 (25-43) median LVFS post 2 DT (%) 31 (25-43) Group 3 (three DT) (n = 39) median baseline LVFS (%) 35 (24-50) median LVFS post 1 DT (%) 34 (25-50) median LVFS post 2 DT (%) 34 (25-50) median LVFS post 3 DT (%) 32 (22-43) Group 4 (four DT) (n = 45) median baseline LVFS (%) 32 (22-49) median LVFS post 1 DT (%) 32 (24-54)